Replication of human retroviruses, such as human immunodeficiency virus type 1 (HIV-1), entails an ordered pattern of viral gene expression. This regulated gene expression is dependent upon the sequence-specific interactions of two viral regulatory proteins, Tat and Rev, with their respective sites on viral RNA. Tat is a transcriptional activator, whereas Rev acts posttranscriptionally to increase the cytoplasmic accumulation of the viral gag-pol and env messenger RNAs (mRNAs).
Because Tat and Rev are critical for viral replication they are attractive targets for therapeutic intervention. To date, three strategies have been attempted to reduce the levels of these viral regulatory proteins or to block their action. First, antisense nucleic acids directed against Rev mRNA have been used to decrease the steady-state level of Rev protein. A second strategy is to sequester (titrate) the regulatory protein by the introduction of a large excess of small "decoy" RNA that contains a high affinity protein-binding site. For example, retroviral vectors expressing the Tat-binding site TAR can inhibit viral replication in cultured cells. A third approach is to express dominant negative mutants of the viral regulatory proteins. For example, Rev derivatives bearing mutations within a discrete C-terminal region abolish Rev activity, and these mutants can inhibit wild-type Rev in a cotransfection assay. A major difficulty inherent in these three strategies is the problem of delivering the therapeutic agent, which is either a nucleic acid or a protein.